Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent

ABSTRACT

The instant invention describes a method for crystallizing (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, such as between about a temperature of 40 DEG  C. and 50 DEG  C.

RELATED APPLICATIONS

This application is based upon U.S. provisional application Ser. Nos.60/037,385 filed Feb. 5, 1997 (abandoned) and Ser. No. 60/042,807 filedApr. 8, 1997 (abandoned).

BACKGROUND OF THE INVENTION

The synthesis of the reverse transcriptase inhibitor (RTI),(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,also known as DMP-266 has been described in U.S. Pat. No. 5,519,021issued on May 21, 1996 and the corresponding PCT International PatentApplication WO 95/20389, which published on Aug. 3, 1995. Additionally,the asymmetric synthesis of an enantiomeric benzoxazinone by a highlyenantioselective acetylide addition and cyclization sequence has beendescribed by Thompson, et al., Tetrahedron Letters 1995, 36, 937-940, aswell as the PCT publication, WO 96/37457, which published on Nov. 28,1996.

The compound was previously crystallized from a heptane-tetrahydrofuran(THF) solvent system. The crystallization procedure required the use ofhigh temperatures (about 90° C.) to dissolve the final product. Crystalsformed by nucleation during the cooling process. The crystals which wereproduced were Form II and are converted to the desired Form I whiledrying under vacuum at 90° C. This crystallization provided minimalpurification and produced material with inconsistent physicalproperties. The final product slurry was extremely difficult to mix andhandle due to its high viscosity and heterogeneous nature.

The instant invention describes a method for crystallizing(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-onefrom a solvent and anti-solvent solvent system and producing thecrystalline product. The desired final crystal form, Form I, can beproduced when using methanol or ethanol. Form II is isolated from2-propanol and can be converted to the desired crystal form at lowdrying temperatures, as low at 40° C.

SUMMARY OF THE INVENTION

A process for the crystallization of a compound of the structuralformula ##STR1## comprising the use of a solvent to effect thedissolution of the compound followed by the addition of an anti-solventto initiate the crystallization.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1.

Flowsheet of the controlled anti-solvent addition crystallizationmethod.

FIG. 2.

Flowsheet of the heel crystallization method.

FIG. 3.

X-ray powder diffraction pattern for Form I of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

FIG. 4.

X-ray powder diffraction pattern for Form II of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

FIG. 5.

X-ray powder diffraction pattern for Form III of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

FIG. 6.

DSC curve for Form III of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

FIG. 7.

TG analysis for Form III of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

DETAILED DESCRIPTION OF THE INVENTION

A process for the crystallization of a compound of the structuralformula ##STR2## comprising the use of a solvent to effect thedissolution of the compound followed by the addition of an anti-solventto initiate crystallization.

A process for the crystallization of a compound of the structuralformula ##STR3## comprising the steps of: (1) dissolving the compound ina solvent in a ratio of about 3.0 ml to about 10.0 ml of solvent to 1gram of the compound;

(2) filtering the solution of the compound to remove any particulatematter;

(3) adding the anti-solvent to the stirring solution at room temperatureover a period of about 30 minutes to about an hour to reach thesaturation point of the solution containing the compound;

(4) adding to the solution a solid seed charge of the compound in theamount of about 2 to about 10 percent by weight to form a slurry;

(5) milling the slurry to reduce the thickness of the slurry;

(6) adding the remaining water to reach the desired solvent compositionof about 30% to about 50% and milling the slurry as needed during theaddition;

(7) slowly cooling the slurry to about 5° C. to about 20° C.;

(8) aging for about 2 to about 16 hours until the supernatantconcentration reaches equilibrium;

(9) milling the slurry, as needed, to reduce the thickness of theslurry;

(10) filtering the milled slurry to isolate a wet cake of thecrystalline compound;

(11) washing the wetcake once with about 1 to about 2 bed volumes of thefinal crystallization solvent composition and then twice with waterusing about 5-10 ml water per gram of compound; and

(12) drying the washed wetcake at about 40° C. to about 90° C. undervacuum for about 1 hour to about 3 days, or until the loss on dryness isless than 0.5 weight percent.

The controlled anti-solvent crystallization process as recited abovewherein the solvent is defined as alcohol, wherein alcohol is a straightor branched chain (C₁ -C₆)-alkanol. A preferred embodiment of thesolvents useful in the controlled anti-solvent crystallization processis (C₁ -C₆)-alkanol, such as, methanol, ethanol, and 2-propanol. Thepreferred alcohol is 2-propanol.

The preferred alcohol is 2-propanol for reasons relating to obtainingconsistent crystal forms. Although methanol and ethanol solvent systemshave been shown to be capable of producing the desired Form I crystalstructure, a slight contamination of Form III crystals in acrystallization slurry in these systems can convert the entire slurry tocontaining exclusively Form III crystals, which are relatively difficultto convert to the desired Form I structure. Any known crystal structureof this compound placed in an about 25% to 35% (v/v) 2-propanol-watersolvent system has been shown to quickly convert to the Form II crystalstructure, which can readily convert to the desired Form I crystalstructure during drying.

The anti-solvent as recited above is defined as a solvent in which thecompound has limited solubility. In the instant process, the preferredanti-solvent is water.

The temperature of the solution during the anti-solvent addition (Step3) was about 20° C. to about 25° C. The temperature of the slurry beingabout 5° C. to about 20° C., and preferrably at about 10° C.

The temperature used during the drying of the washed wetcake (Step 12)is about 40° C. to about 90° C., and preferrably about 40° C. to about60° C.

The solvent system (solvent plus anti-solvent) used ranged from about30% to about 50% solvent volume to anti-solvent volume (v/v) ratio. Thetotal volume of the solvent system ranging from about 12 to about 20 mlof the solvent system per gram of the compound. The solvent volume toanti-solvent volume ratio for selected solvent systems is as follows: 1)an ethanol-water solvent system is about 30% to about 40% ethanol towater v/v ratio; 2) a methanol-water solvent system is about 40% toabout 50% methanol to water v/v ratio; and 3) an 2-propanol-watersolvent system is about 25% to about 35% 2-propanol to water v/v ratio.The perferred solvent system is 2-propanol-water used in about a 30%volume to volume ratio and a total solvent system volume of about 15 mlper gram of the compound.

A process for the crystallization of a compound of the structuralformula ##STR4## comprising the steps of: (1) mixing about 10% to about20% by weight of the final amount of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-onein the desired v/v ratio of solvent to anti-solvent at about 20° C. toform the heel or retaining a final slurry from a previous batch;

(2) adding the solution of solvent and (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,and anti-solvent to the heel simultaneously at constant rates over about6 hours maintaining the v/v ratio of solvent to anti-solvent;

(3) milling the slurry during the addition to reduce the thickness ofthe slurry;

(4) cooling the slurry to about 10° C. over about 3 hours and agingslurry until the supernatant concentration reaches equilibrium;

(5) filtering the milled slurry to isolate a wet cake of the crystallinecompound;

(6) washing the wetcake once with about 1 to about 2 bed volumes of thefinal crystallization solvent composition and then twice with waterusing about 5 ml to about 10 ml water per gram of compound; and

(7) drying the washed wetcake at about 40° C. to about 90° C. undervacuum for about 1 hour to about 3 days, or until the loss on dryness isless then 0.5 weight percent.

The heel crystallization process as recited above wherein the solvent isdefined as acetonitrile, dimethyl acetamide, dimethyl formamide oralcohol. A preferred embodiment of the solvents useful in the controlledanti-solvent crystallization process is alcohol, wherein alcohol isdefined as (C₁ -C₆)-alkanol, such as, methanol, ethanol, and 2-propanol.The preferred alcohol is 2-propanol.

The anti-solvent as recited above is defined as a solvent in which thecompound has limited solubility. In the heel crystallization process thepreferred anti-solvent is water.

The process as recited above wherein the temperature of the solutionduring the anti-solvent addition is about 5° C. to about 20° C.

The temperature used during the drying of the washed wetcake is about40° C. to about 90° C., and preferrably about 40° C. to about 60° C.

The solvent system (solvent plus anti-solvent) used ranges from about30% to about 50% solvent volume to anti-solvent volume (v/v) ratio. Thetotal volume of the solvent system ranging from about 12 to about 20 mlof the solvent system per gram of the compound. The solvent toanti-solvent volume to volume ratio for selected solvent systems is asfollows: 1) an ethanol-water solvent system is about 30% to about 40%ethanol to water v/v ratio; 2) a methanol-water solvent system is about40% to about 50% methanol to water v/v ratio; and 3) an 2-propanol-watersolvent system is about 25% to about 35% 2-propanol to water v/v ratio.The perferred solvent system is 2-propanol-water used in about a 30%volume to volume ratio and a total solvent system volume of about 15 mlper gram of the compound.

FIGS. 3, 4 and 5 are the X-ray powder diffraction (XRPD) patterns forForms I, II and III, respectively. These XRPD patterns were recordedusing an automated X-ray diffractometer APD 3720 with copper K alpharadiation. The crystal forms I and II of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-onewhich are characterized by the noted X-ray powder diffraction patternshave the following key diffraction peaks (2Θ) with intensities(I/I_(max), %) of 10 or greater:

    ______________________________________                                        Form I         Form II Form III                                               ______________________________________                                        6.0800         3.6375  7.2150                                                   6.3900 6.3325 10.9675                                                         10.3950 11.0725 13.7275                                                       10.9875 12.7750 14.5325                                                       12.2850 13.3275 16.7275                                                       13.1900 14.2925 19.0675                                                       14.1700 16.1200 19.6550                                                       15.1925 16.8975 20.8250                                                       16.9000 18.5025 21.7450                                                       18.4375 19.1975 22.2825                                                       19.2275 19.6025 22.8475                                                       20.0925 20.6650 23.1750                                                       21.2100 21.3250 23.8850                                                       22.3600 22.6150 24.4900                                                       23.0725 23.1775 24.9075                                                       24.8900 24.4075 25.8200                                                       25.9500 24.9650 27.0325                                                       26.3575 26.0100 27.6050                                                       27.2550 26.8550 29.2975                                                       28.1150 27.6400 30.2600                                                       28.5850 28.3675 30.7300                                                       29.1325 29.1725 31.3125                                                       29.5625 29.6325 33.3975                                                       30.6850 30.5650 38.4325                                                       32.3725 31.8950 39.2100                                                       38.3125 33.8225                                                             ______________________________________                                    

Additionally, these crystal forms are characterized by peaks withvarying D-spacings. Form I is characterized by peaks with D-spacings of:14.5, 8.5, 8.0, 7.2, 6.7, 6.2, 5.2, 4.6, 4.4, 4.2, and 3.6 angstroms.Form II is characterized by peaks with D-spacings of: 24.3, 13.9, 8.0,6.9, 6.6, 5.5, 4.6, 4.5, 4.3, 4.2, 3.9, 3.6, 3.4, 3.3, and 3.2angstroms. Form III is characterized by peaks with D-spacings of: 12.2,8.1, 6.4, 6.1, 4.7, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, and 3.0angstroms.

Thermogravimetric analysis results of Form III (FIG. 7) indicated therewas no significant weight loss observed from 43° C. to about 137° C.This result is indicative of an anhydrous or unsolvated crystal form.

The differential scanning calorimetry (DSC) results obtained for FormIII show an endotherm with an extrapolated onset temperature of 117° C.,a peak temperature of 118° C., and an enthalpy of 34 J/g, this isfollowed by an exotherm with a peak temperature of 120° C. and anenthalpy of 23 J/g. A second endotherm with an extrapolated onsettemperature of 138° C., a peak temperature of 139° C., and an enthalpyof 55 J/g is also observed. The first endotherm is associated with themelting of Form III, which subsequently crystallizes to Form I duringthe exothermic event. The second endothermic event is associated withthe melting of Form I.

A process for isolating(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,the final product from solutions containing an organic solvent and waterhas been developed. In this process water serves as an anti-solvent toproduce a solid product from material dissolved in organic solvent. Thefinal solvent composition is chosen to balance yield loss, purification,and slurry handling properties.

For methanol solvent systems about 40% to about 50% volume to volume(v/v) solvent to anti-solvent (water) has been present in the finalslurry. Ethanol solvent systems have contained about 30% to about 40%v/v solvent to anti-solvent, and 2-propanol solvent systems have usedabout 25% to about 35% (v/v) solvent to anti-solvent. The total amountof liquid (alcohol and water) ranges from 12-20 ml/(g solid). Thecrystallizations are typically performed between 20-25° C., and someslurries have been cooled to 5-10° C. before being filtered. Followingthe filtration, the wetcake is washed with approximately one bed volume(the approximate volume of the wetcake) of the final crystallizationsolvent composition. The wetcake is then washed with at least 2 bedvolumes of deionized (DI) water.

The rate at which the product is precipitated is controlled by eitherslowly adding the water to a saturated system following a seed charge(anti-solvent addition) or simultaneously adding the product in alcoholand water at controlled rates to an existing product slurry (heelcrystallization).

For the anti-solvent process (FIG. 1), enough water is first added tothe organic solvent solution containing the product over 0.5-2 hours tosaturate the system in final product. A solid charge of final product isthen added to the system as seed (2-10% of the initial amount ofproduct). The seed should be Form I (the crystal form associated withdry final product) for ethanol and methanol systems, and Form II seed(the crystal form generated from a THF/heptane crystallization) is usedfor 2-propanol systems. The resultant slurry is aged for 0.5-2 hours toestablish a seed bed. The remaining water is then added over 2-4 hoursin a controlled manner. The slurry is then aged for 2-20 hours andcooled to the desired final temperature during the age, allowing thesupernatant to reach equilibrium.

For the heel process (FIG. 2), a slurry at the desired final solventcomposition is mixed while adding the product dissolved in alcohol andwater at controlled relative rates to maintain a constant solvent ratio.The slurry (the crystalline compound in the final desired solventsystem) is often 10-20% of the product from a prior run. The totalcharge is typically performed over 4-6 hours at 20-25° C. The slurry isthen aged for several hours at the desired final temperature beforebeing filtered to allow the supernatant to reach equilibrium. Followingthe filtration, the wetcake is washed with approximately one bed volumeof a clean alcohol/water mixture matching the final crystallizationconditions. The wetcake is then washed with at least 2 bed volumes of DIwater.

Further control of the crystal size and slurry viscosity is achieved byusing a wet-mill on slurries with excessively long particles and/orextremely thick consistencies. The product typically forms rod shapedcrystals which grow much faster in the axial direction than the radialdirection. It is understood that the reference to `thickness` will referto the crystal size and consistency of the slurry. The mill has beenshown to reduce the length of the long crystals and produce a thinslurry from a thick slurry which contains many agglomerates of crystals.On the laboratory scale, the entire slurry can be milled batch-wise whendesired. At larger scales, the wet-mill can be used on a recycle loopcirculating around the crystallization vessel. An in-line particle sizemeasurement and viscosity measurements could be coordinated to controlthe mill. Varying the temperature of the slurry through a range of 5° C.to 50° C. cycles has also been shown to be a useful way of modifying thecrystal size and shape.

The solvents useful in this method include alcohol, acetonitrile (heelprocess only), dimethyl formamide (heel process only), and dimethylacetamide (heel process only), The preferred solvent is an alcoholselected form methanol, ethanol or 2-propanol.

This crystallization process is advantageous over the prior method. Theinstant method allows one to isolate a crystalline product withconsistent physical properties namely the ability to produce the desiredcrystal form of the product or convert to Form I with mild dryingconditions (heating to about 40 to 60° C.). The alcohol-watercrystallizations have also been shown to reject some impurities carriedforward from the chemical synthesis. The final product slurry is lessviscous and more homogenous with the instant process and is thus easierto mix and handle.

The following examples are meant to be illustrative of the presentinvention. These examples are presented to exemplify the invention andare not to be construed as limiting the scope of the invention.

EXAMPLE 1

Controlled Anti-Solvent Addition Crystallization Process 400 g ofDMP-266 starting material is dissolved in 2.400 L of ethanol. SeeFIG. 1. The solution is filtered to remove extraneous matter. 2.088 L ofdeionized (DI) water is added to the solution over 30 to 60 minutes. 20g of DMP-266 seed is added to the solution. The seed bed is aged for 1hour. The use of Intermig agitators is preferred to mix the slurry. Ifrequired (by the presence of extremely long crystals or a thick slurry),the slurry is wet-milled for 15-60 seconds. 1.512 L of DI water is addedto the slurry over 4 to 6 hours. If required (by the presence ofextremely long crystals or a thick slurry), the slurry is wet-milled for15 to about 60 seconds during the addition. The slurry is aged for 1 to3 hours before being cooled to 10° C. over 3 hours. The slurry is agedfor 2 to 16 hours until the product concentration in the supernatantremains constant. The slurry is filtered to isolate a crystalline wetcake. The wet cake is washed with 1 to 2 bed volumes of 40% ethanol inwater and then twice with 2 L of DI water each. The washed wet cake isdried under vacuum at 50° C.

EXAMPLE 2

Semi-Continuous Heel Crystallization Process

400 g of DMP-266 starting material is dissolved in 2.400 L of ethanol.See FIG. 2. A heel slurry is produced by mixing 20 g of DMP-266 in 0.3 Lof 40% (v/v) ethanol in water. The dissolved batch and 3.6 L of DI waterare simultaneously charged to the heel slurry at constant rates over 6hours to maintain a constant solvent composition in the crystallizer.Use of Intermig agitators during the crystallization is preferred.During this addition the slurry is wet-milled when the crystal lengthsbecome excessively long or the slurry becomes too thick. The slurry iscooled to about 10° C. over 3 hours. The slurry is aged for 2 to 16hours until the product concentration in the supernatant remainsconstant. The slurry is filtered to isolate a crystalline wet cake. Thewet cake is washed with 1 to 2 bed volumes of 40% ethanol in water andthen twice with 2 L of DI water each. The washed wet cake is dried undervacuum at 50° C.

EXAMPLES 3-8

Following the crystallization procedures described in Examples 1 and 2above using the solvents noted in the table below in the amounts recitedDMP-266 can be crystallized.

    ______________________________________                                                                         Anti-                                           ml solvent per ml H.sub.2 O per g. solvent Heel                              Ex #: Solvent g. DMP-266* DMP-266*  Process Process                         ______________________________________                                        EX. 3: Acetonitrile                                                                      3.6-8.0    7.2-14     --    X                                        EX. 4: Dimethyl 3.6-8.0 7.2-14 -- X                                           acetamide                                                                     EX. 5: Dimethyl 3.6-8.0 7.2-14 -- X                                           formamide                                                                     EX. 6: Ethanol 3.6-8.0 7.2-14 X X                                             EX. 7: Methanol 4.8-10  5.4-12 X X                                            EX. 8: 2-Propanol 3.0-7.0 7.8-15 X X                                        ______________________________________                                         *The sum of the amounts of solvent and water should be at least 12 ml/g.      The currently preferred concentration is 15 ml/g.                             -- method did not work.                                                       X method worked.                                                         

EXAMPLE 9

Crystallization of DMP-266 from 30% 2-Propanol in Water using a ratio of15 ml solvent per gram DMP-266 Using Controlled Anti-Solvent Addition ona 400 g Scale

400 g. of DMP-266 starting material is dissolved in 1.9 L of 2-propanol.The solution is filtered to remove extraneous matter. 1.95 L ofdeionized (DI) water is added to the solution over 30 to 60 minutes. 10g. to 20 g. of DMP-266 seed (Form II wetcake) is added to the solution.The seed bed is aged for 1 hour. The use of Intermig agitators ispreferred to mix the slurry. If required (by the presence of extremelylong crystals or a thick slurry), the slurry is wet-milled for 15-60seconds. 2.25 L of DI water is added to the slurry over 4 to 6 hours. Ifrequired (by the presence of extremely long crystals or a thick slurry),the slurry is wet-milled for 15-60 seconds during the addition. Theslurry is aged for 2 to 16 hours until the product concentration in thesupernatant remains constant. The slurry is filtered to isolate acrystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of30% 2-propanol in water and then twice with 1 bed volume of DI watereach. The washed wet cake is dried under vacuum at 50° C.

EXAMPLE 10

Crystallization of DMP-266 from 30% 2-Propanol in Water using a ratio of15 ml solvent per gram DMP-266 Using a Semi-Continuous Process on a 400g Scale

400 g. of DMP-266 starting material is dissolved in 1.8 L of 2-propanol.A heel slurry is produced by mixing 20 g. of Form II DMP-266 in 0.3 L of30% (v/v) 2-propanol in water or retaining part of a slurry from aprevious crystallization in the crystallizer. The dissolved batch and4.2 L of DI water are simultaneously charged to the heel slurry atconstant rates over 6 hours to maintain a constant solvent compositionin the crystallizer. Use of Intermig agitators during thecrystallization is preferred. During this addition the slurry iswet-milled when the crystal lengths become excessively long or theslurry becomes too thick. The slurry is aged for 2 to 16 hours until theproduct concentration in the supernatant remains constant. The slurry isfiltered to isolate a crystalline wet cake. The wet cake is washed with1 to 2 bed volumes of 30% 2-propanol in water and then twice with 1 bedvolume of DI water each. The washed wet cake is dried under vacuum at50° C.

What is claimed is:
 1. A process for the crystallization of a compoundof the structural formula ##STR5## comprising the steps of: (1)dissolving the compound in a solvent in a ratio of about 3.0 ml to about10.0 ml of solvent to 1 gram of the compound;(2) filtering the solutionof the compound to remove any particulate matter; (3) adding theanti-solvent to the stirring solution at room temperature over a periodof about 30 minutes to about an hour to reach the saturation point ofthe solution containing the compound; (4) adding to the solution a solidseed charge of the compound in the amount of about 2 to about 10 percentby weight to form a slurry; (5) milling the slurry to reduce thethickness of the slurry; (6) adding the remaining water to reach thedesired solvent composition of about 30% to about 50% and milling theslurry as needed during the addition; (7) slowly cooling the slurry toabout 5° C. to about 20° C.; (8) aging for about 2 to about 16 hoursuntil the supernatant concentration reaches equilibrium; (9) milling theslurry, as needed, to reduce the thickness of the slurry; (10) filteringthe milled slurry to isolate a wet cake of the crystalline compound;(11) washing the wetcake once with about 1 to about 2 bed volumes of thefinal crystallization solvent composition and then twice with waterusing about 5-10 ml water per gram of compound; and (12) drying thewashed wetcake at about 40° C. to about 90° C. under vacuum for about 1hour to about 3 days, or until the loss on dryness is less than 0.5weight percent.
 2. The process as recited in claim 1 wherein the solventis defined as (C₁ -C₆)-alcohol.
 3. The process as recited in claim 2wherein the anti-solvent is defined as water.
 4. The process as recitedin claim 1 wherein the temperature during the anti-solvent addition(Step 3) is about 20° C. to about 25° C.
 5. The process as recited inclaim 1 wherein the temperature used during the drying of the washedwetcake (Step 12) is about 40° C. to about 60° C.
 6. The process asrecited in claim 3 wherein the solvent volume to anti-solvent volumeratio used is about 30% to about 50%.
 7. The process as recited in claim6 wherein the (C₁ -C₆)-alcohol is selected from methanol, ethanol and2-propanol.
 8. The process as recited in claim 7 wherein the (C₁-C₆)-alcohol is 2-propanol.
 9. The process as recited in claim 8 whereinthe total solvent system volume per gram of compound is about 12 ml/gmto about 20 ml/gm of about a 30% to about a 40% ethanol to water solventto anti-solvent volume to volume ratio.
 10. The process as recited inclaim 6 wherein the total solvent system volume per gram of compound isabout 12 ml/gm to about 20 ml/gm of about 40% to about 50% methanol towater solvent to anti-solvent volume to volume ratio.
 11. The process asrecited in claim 6 wherein the total solvent system volume per gram ofcompound is about 12 ml/gm to about 20 ml/gm of about 25% to about 35%2-propanol to water solvent to anti-solvent volume to volume ratio. 12.The process as recited in claim 10 wherein the total solvent systemvolume per gram of compound is about 15 ml/gm of about 30% 2-propanol towater solvent to anti-solvent volume to volume ratio.
 13. A process forthe crystallization of a compound of the structural formula ##STR6##comprising the steps of: (1) mixing about 10% to about 20% by weight ofthe final amount of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-onein the desired v/v ratio of solvent to anti-solvent at about 20° C. toform the heel;(2) adding the solution of solvent and(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one,and anti-solvent to the heel simultaneously at constant rates over about6 hours maintaining the v/v ratio of solvent to anti-solvent; (3)milling the slurry during the addition to reduce the thickness of theslurry; (4) cooling the slurry to about 10° C. over about 3 hours andaging slurry until the supernatant concentration reaches equilibrium;(5) filtering the milled slurry to isolate a wet cake of the crystallinecompound; (6) washing the wetcake once with about 1 to about 2 bedvolumes of the final crystallization solvent composition and then twicewith water using about 5 ml to about 10 ml water per gram of compound;and (7) drying the washed wetcake at about 40° C. to about 90° C. undervacuum for about 1 hour to about 3 days, or until the loss on dryness isless then 0.5 weight percent.
 14. The process as recited in claim 13wherein solvent is defined as acetonitrile, dimethyl acetamide, dimethylformamide or alcohol.
 15. The process as recited in claim 14 wherein theanti-solvent is defined as water.
 16. The process as recited in claim 15wherein the alcohol solvent is defined as (C₁ -C₆)-alcohol.
 17. Theprocess as recited in claim 13 wherein the temperature of the solutionduring the compound-solvent solution/anti-solvent addition (Step 2) isabout 5° C. to about 20° C.
 18. The process as recited in claim 13wherein the temperature used during the drying of the washed wetcake(Step 7) is about 40° C. to about 60° C.
 19. The process as recited inclaim 16 wherein the alcohol to anti-solvent volume to volume ratio usedis about 30% to about 50%.
 20. The process as recited in claim 19wherein the alcohol solvent is selected from methanol, ethanol and2-propanol.
 21. The process as recited in claim 20 wherein the solventis 2-propanol.
 22. The process as recited in claim 20 wherein the totalsolvent system volume per gram of compound is about 12 ml/gm to about 20ml/gm of about a 30% to about a 40% ethanol to water solvent toanti-solvent volume to volume ratio.
 23. The process as recited in claim20 wherein the total solvent system volume per gram of compound is about12 ml/gm to about 20 ml/gm of about 40% to about 50% methanol to watersolvent to anti-solvent volume to volume ratio.
 24. The process asrecited in claim 21 wherein the total solvent system volume per gram ofcompound is about 12 ml/gm to about 20 ml/gm of about 25% to about 35%2-propanol to water solvent to anti-solvent volume to volume ratio. 25.The process as recited in claim 23 wherein the total solvent systemvolume per gram of compound is about 15 ml/gm of about 30% 2-propanol towater solvent to anti-solvent volume to volume ratio.